Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. For example, current treatments for acquired immunodeficiency syndrome (AIDS) include administration of compounds such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-.beta.-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine (AZT), and adriamycin, all of which inhibit viral DNA synthesis, see, e.g., Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49. Alternatively, compounds such as AL-721 or polymannoacetate may be administered to prevent human immunodeficiency virus (HIV) from penetrating the host cell. Also, compounds which treat the opportunistic infections caused by the immunosupression resulting from HIV infection are known. However, none of the current AIDS treatments has proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including platelet count, renal toxicity, and bone marrow cytopenia.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral bioavailability and in vivo stability of candidate inhibitors.
Retrovirus genome encodes a protease that can accomplish the proteolytic processing of one or more polyprotein precursors, such as the polyprotein precursors encoded by the pol and gag genes. See Wellink Arch. Virol. 1988, 98, 1. Retroviral proteases most commonly process the polyprotein precursor encoded by the gag gene into its core proteins, and process the polyprotein precursor encoded by the pol gene into the enzymes reverse transcriptase and retroviral protease.
The correct processing of precursor polyproteins by retroviral protease is necessary for assembly of infectious virions. It has been shown that the in vitro mutagenesis that produces a protease-defective virus also leads to the production of immature core forms of the virus which lack infectivity. See Crawford et al. J. Virol. 1985, 53, 899 and Katoh et al. Virology 1985, 145, 280. Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy, see Mitsuya, Nature 1987, 325, 775. The inhibition of viral protease provides a method for blocking viral replication, and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.
Moore Biochem. Biophys. Res. Commun. 1989, 159, 420 discloses peptidyl inhibitors of HIV protease. Erickson, PCT Patent Application Publication No. WO 89/10752 discloses derivatives of peptides that are inhibitors of HIV protease. U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. PCT Patent Application Publication No. WO 87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent. PCT Patent Application Publication No. WO 93/07128, the disclosure of which is hereby incorporated herein by reference, discloses synthetic procedures for preparing HIV protease inhibitors.
A large number of compounds, e.g., renin, have been reported to be proteases inhibitors. However, many of these compounds suffer from an inability to reach their targets (bioavailability), particularly if oral administration is desired, and thus are not altogether satisfactory therapeutic agents. This poor activity has been variously ascribed to the relatively high molecular weight and size of most protease inhibitors, to solubility properties that work against free transport of the inhibitors, and to vulnerability of the peptide bonds in the inhibitors to in vivo cleavage by mammalian proteases, resulting in the inhibitor and fragments thereof becoming bound to human serum.
The present invention concerns novel substituted bicyclic phosphoramides and derivatives thereof, which are capable of inhibiting viral protease and thereby provide a means of combating virus induced diseases, such as AIDS. The substituted bicyclic phosphoramides of the invention provide significant improvements over protease inhibitors that are known in the art. The substituted bicyclic phosphoramides and derivatives of the present invention afford distinct benefits in overcoming problems of recognized protease inhibitors, in that they do not contain peptide bonds, and can be hydrophilic yet still inhibit viral protease enzyme. The inhibitors of the invention are also of low molecular weight, and therefore can be expected to have good oral absorption properties in mammals.
Additionally, known inhibitors of other non-HIV proteases do not inhibit HIV protease. The structure-activity requirements of such inhibitors differ from those of HIV protease inhibitors. The substituted bicyclic phosphoramides and derivatives thereof of the invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.
The invention also provides materials useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit viral replication and/or HIV protease. These would be provided as a commercial kit comprising a compound provided by this invention.